Inhibition of P-selectin attenuates neutrophil-mediated myocardial dysfunction in isolated rat heart

The expression of P-selectin on postischemic endothelium after reperfusion has been shown to trigger neutrophil attachment and the subsequent inflamma tory responses. Extensive studies have demonstrated that P-selectin is invo lved in the progression of neutrophil-mediated myocardial infarction and no -reflow phenomenon. In the present study, we examined the effects of select in inhibitors, sialyl Lewis X-oligasaccharide and anti-P-selectin monoclona l antibody, PB1.3 on neutrophil-dependent left ventricular dysfunction in i solated rat heart. The hearts were subjected to global ischemia for 20 min and then reperfused for 45 min with rat plasma in the presence of human neu trophils during the first 5 min of the reperfusion, Left ventricular develo ped pressure and other parameters of the left ventricular function deterior ated throughout the reperfusion period in a neutrophil-dependent manner. In contrast, the coronary flow was reduced early on (<15 min) but recovered t o the level in the hearts reperfused with no neutrophils 45 min after the r eperfusion. We examined the effects of selectin inhibitors under experiment al conditions in which the hearts were perfused with 30 million neutrophils . The treatment with sialyl Lewis X-oligosaccharide at a dose of 0.3 mg/min resulted in amelioration of left ventricular developed pressure to 57.2 +/ - 14%, compared to 26.1 +/- 4.3% in the saline-treated group (P < 0.05). Si milarly, the treatment with mouse anti-human P-selectin monoclonal antibody (IgG1) PB1.3 at a dose of 0.6 mg/min resulted in the prominent recovery of left ventricular developed pressure after 45 min of reperfusion (59.9 +/- 9.3% vs. 26.1 +/- 4.3% in the saline-treated group, P < 0.05). PB1.3 also a ttenuated the elevation of left ventricular end-diastolic pressure compared to that of the saline-treated group during the reperfusion period. Moreove r, the treatment with PB1.3 ameliorated the recovery of coronary flow until 10 min after the reperfusion and the recovery of coronary flow 10 min afte r the reperfusion was 55.2 +/- 9.2%, as compared to 28.2 +/- 7.7% in saline -treated hearts (P < 0.05). To our knowledge, this is the first direct demo nstration that the specific inhibition of P-selectin results in the inhibit ion of neutrophil-mediated left ventricular dysfunction or myocardial stunn ing. (C) 1999 Elsevier Science B.V. All rights reserved.